First 18F-Labeled Pentixafor-Based Imaging Agent for PET Imaging of CXCR4 Expression In Vivo

Andreas Poschenrieder, Theresa Osl, Margret Schottelius, Frauke Hoffmann, Martina Wirtz, Markus Schwaiger, Hans-Jürgen Wester, Andreas Poschenrieder, Theresa Osl, Margret Schottelius, Frauke Hoffmann, Martina Wirtz, Markus Schwaiger, Hans-Jürgen Wester

Abstract

In vivo quantification of CXCR4 expression using [68Ga]pentixafor for positron emission tomography (PET) imaging has gained significant clinical interest as CXCR4 plays a fundamental role in oncology and possesses potential prognostic value when overexpressed. To combine the excellent CXCR4-targeting properties of pentixafor-based tracers with the favorable radionuclide properties of 18F for high-resolution PET imaging, we developed an Al18F-labeled 1,4,7-triazacyclononane-triacetic acid (NOTA) analog of pentixather. Al18F-labeling of NOTA-pentixather was performed in aqueous dimethyl sulfoxide (DMSO) at pH = 4 (105°C, 15 minutes). CXCR4 affinities were determined in competitive binding assays, and both biodistribution and small-animal PET studies were performed in Daudi lymphoma-bearing mice. Under non-optimized conditions, [18F]AlF-NOTA-pentixather was obtained in radiochemical yields of 45.5% ± 13.3% and specific activities of up to 24.8 GBq/μmol. Compared with [natGa]pentixafor, [natF]AlF-NOTA-pentixather showed 1.4-fold higher CXCR4 affinity. [18F]AlF-NOTA-pentixather displayed high and CXCR4-specific in vivo uptake in Daudi xenografts (13.9% ± 0.8% injected dose per gram [ID/g] at 1 hour post injection [p.i.]). Because of its enhanced lipophilicity (logP = -1.4), [18F]AlF-NOTA-pentixather showed increased accumulation in the gall bladder and intestines. However, tumor/background ratios of 7.0 ± 1.2, 2.0 ± 0.3, 2.2 ± 0.4, 16.5 ± 6.5, and 29.2 ± 4 for blood, liver, small intestine, gut, and muscle, respectively, allowed for high-contrast visualization of Daudi tumors using PET (1 hour p.i.). The relatively straightforward radiosynthesis and efficient CXCR4 targeting of [18F]AlF-NOTA-pentixather demonstrate the successful implementation of 18F-complexation chemistry and pentixather-based CXCR4 targeting. Upon pharmacokinetic optimization, this class of tracers holds great promise for future application in humans.

Keywords: 18F; CXCR4; NOTA; PET; cancer.

Conflict of interest statement

Conflict of Interest: None Reported.

Figures

Figure 1.
Figure 1.
Structures of pentixafor (left) and NOTA/NODA-NCS-pentixather (right).
Scheme 1.
Scheme 1.
Aqueous radiofluorination of NOTA-pentixather.
Figure 2.
Figure 2.
Representative competitive binding curve of [natF]AlF-NOTA-pentixather using Jurkat T-cells and [125I]FC131 as the radioligands (left panel), as well as total cellular uptake and internalization of [18F]AlF-NOTA-pentixather, compared with [68Ga]pentixafor in hCXCR4-transfected Chem-1 cells (right panel). Data are corrected for nonspecific binding/internalization in the presence of 100 μM AMD3100.
Figure 3.
Figure 3.
Biodistribution of [18F]AlF-NOTA-pentixather (60 minutes post injection [p.i.], n = 4, red bars) and [68Ga]pentixafor (1.5 hour p.i., n = 6, gray bars) in Daudi xenograft-bearing CB-17 SCID mice. To show CXCR4-specific tumor accumulation of [18F]AlF-NOTA-pentixather, 50 μg of AMD3100 was coinjected (60 minutes p.i., n = 4, white bars). Data are given in % ID/g tissue and are means ± SD.
Figure 4.
Figure 4.
Tumor-to-organ ratios of [18F]AlF-NOTA-pentixather (red bars) compared with those of [68Ga]pentixafor (white bars). Data are expressed as mean ± SD (n = 4).
Figure 5.
Figure 5.
[18F]AlF-NOTA-pentixather PET/CT images of Daudi xenograft-bearing CB-17 SCID mice at 60 minutes p.i.; tracer only (A) and coinjection of 2 mg/kg AMD3100 (B). Mice were injected with 0.30 MBq of [18F]AlF-NOTA-pentixather (corresponding to 195 pmol/0.251 μg peptide).

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